Case series of congenital pseudarthrosis of the tibia unfulfilling neurofibromatosis type 1 diagnosis: 21% with somatic NF1 haploinsufficiency in the periosteum

Zheng, Yu; Zhu, Guoqiang; Liu, Yaoxi; Zhao, Wei; Yang, Yongjia; Luo, Zhenqing; Fu, Yuyan; Mei, Haibo; Hu, Zhengmao

doi:10.1007/s00439-021-02429-2

Cited by 6 publications

(7 citation statements)

References 75 publications

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“…In the present study, we did not detect the lesion tissue. Zheng et al (2022) collected the periosteum tissue from the pseudarthrosis site of six patients with NF1-CPT (i.e., probands) and their unaffected parents. They found that five of six NF1-CPT patients (83.3%) had NF1 inactivation in tissues.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we had to admit that WES may not detect all the NF1 variants. For instance, non-coding variants from the regulating area of NF1 may be among the undetected genetic regions ( Zheng et al, 2022 ). Therefore, we recommended using comprehensive detection and analysis of other variants using both the lesion tissue and the blood of patients with and without NF1 CPT.…”

Section: Discussionmentioning

confidence: 99%

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Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Zhang

et al. 2022

Front. Genet.

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Congenital pseudarthrosis of the tibia (CPT) is a rare congenital bone malformation, which has a strong relationship with Neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant disease leading to multisystem disorders. Here, we presented the genotypic and phenotypic characteristics of one unique case of a five-generation Chinese family. The proband was CPT accompanied with NF1 due to NF1 mutation. The proband developed severe early-onset CPT combined with NF1 after birth. Appearance photos and X-ray images of the left limb of the proband showed significant bone malformation. Slit-lamp examination showed Lisch nodules in both eyes of the proband. Whole-exome sequencing (WES) and Sanger sequencing confirmed the truncation variant of NF1 (c.871G>T, p. E291*). Sequence conservative and evolutionary conservation analysis indicated that the novel mutation (p.E291*) was highly conserved. The truncated mutation led to the loss of functional domains, including CSRD, GRD, TBD, SEC14-PH, CTD, and NLS. It may explain why the mutation led to a severe clinical feature. Our report expands the genotypic spectrum of NF1 mutations and the phenotypic spectrum of CPT combined with NF1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Zhang

et al. 2022

Front. Genet.

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“…28.23292011 doi: medRxiv preprint associated with neurofibromatosis type 1(NF1), a common autosomal dominant genetic disorder [3]. Previous research has reported that 80%-84% of CPT cases present with NF1(NF1-CPT) in the epidemiology and the genomic mutations in the NF1 gene have been linked to CPT in the genomics [4][5][6][7]. The double inactivation model has been proposed as a hypothesis to explain these associations [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Molecular Landscape of Congenital Pseudoarthrosis of the Tibia: Insights from a Comprehensive Analysis of 162 Probands

Zhu,

Li,

Zheng

et al. 2023

Preprint

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Congenital pseudarthrosis of the tibia (CPT, HP:0009736), commonly known as bowing of the tibia, is a rare congenital tibia malformation characterized by spontaneous tibial fractures and the difficulty of reunion after tibial fractures during early childhood, with a very low prevalence between 1/250,000 ~ 1/140,000. While 80% ~ 84% of CPT cases present with neurofibromatosis type 1, caused by the mutations in NF1, the underlying cause of CPT is still unclear. Considering the congenital nature and the low prevalence of CPT, we hypothesized that the rare genomic mutations may contribute to CPT. In this study, we conducted whole exome sequencing on 159 patients with CPT and full-length transcriptome sequencing on an additional 3 patients with CPT. The data analysis showed there were 179 significantly up-regulated genes which were enriched in 40 biological processes among which 21 biological processes hold their loss of function (LoF) excesses between 159 cases against 208 controls from 1000 Genomes Project. From those 21 biological processes with LoF excesses, there were 259 LoF-carried genes among which 40 genes with 56 LoF variations in 63 patients were enriched in osteoclast differentiation pathway (hsa04380) with its 3 directly regulated pathways including MAPK signaling pathway (hsa04010), calcium signaling pathway (hsa04020) and PI3K-Akt signaling pathway (hsa04151), as well as fluid shear stress and atherosclerosis pathway (hsa05418) while 12 patients carried 9 LoF variations in the NF1 gene. The rare LoF variations in these pathways accounted for ~39.6% of this CPT cohort. These findings shed light on the novel genetic mutations and molecular pathways involved in CPT, providing a new framework for understanding how the genetic variations regulate the biological processes in the pathology of CPT and indicating potential next directions to further elucidate the pathogenesis of CPT.

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“…Congenital pseudarthrosis of the tibia (CPT) is one of the most challenging problems in pediatric orthopedics [ 1 , 2 ]. The incidence rate of CPT is between 1:140,000 and 1:250,000 births.…”

Section: Introductionmentioning

confidence: 99%

“…mRNAs are involved in CPT progression by modulating the osteogenic differentiation of MSCs [ 2 ]. HOXD8 is the pivotal gene in cancer-related pathways and could regulate the osteogenic differentiation of MSCs [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

miR-30a inhibits the osteogenic differentiation of the tibia-derived MSCs in congenital pseudarthrosis via targeting HOXD8

Huang

Zhu

et al. 2022

Regenerative Therapy

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Case series of congenital pseudarthrosis of the tibia unfulfilling neurofibromatosis type 1 diagnosis: 21% with somatic NF1 haploinsufficiency in the periosteum

Cited by 6 publications

References 75 publications

Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation

Unraveling the Molecular Landscape of Congenital Pseudoarthrosis of the Tibia: Insights from a Comprehensive Analysis of 162 Probands

miR-30a inhibits the osteogenic differentiation of the tibia-derived MSCs in congenital pseudarthrosis via targeting HOXD8

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